This invention relates to hydrazinyl and nitrogen oxide pyrazoles, methods of treatment and pharmaceutical compositions for the treatment of cyclooxygenase mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock.
Sulfonyl pyrazoles are useful in the treatment of cyclooxygenase (COX) mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. Two forms of COX are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, et. al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. The therapeutic use of conventional COX inhibitors are limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition. Preferred compounds of the invention are selective COX-2 inhibitors.
A variety of sulfonylpyrazoles that inhibit COX have been described in patent publications WO 97/11704, WO 01/40216, EP 1104758, EP 1104759 and EP 1104760; U.S. Non-Provisional patent application Ser. No. 09/798,752, filed Mar. 2, 2001; and U.S. Non-Provisional patent application Ser. No. 09/824,550, filed Apr. 2, 2001.
Filed simultaneously with the present application on Nov. 2, 2001, are United States Provisional Applications entitled “Heterocyclo-Alkylsulfonyl Pyrazoles”; “5-Heteroatom-Substituted Pyrazoles”; “5-Heterocyclo-Pyrazoles”; and “5-(Alkylidene-Cycloalkyl)- and 5-(Alkylidene-Heterocyclyl)-Pyrazoles”, which refer to certain pyrazole COX-2 inhibitors. The aforesaid applications are herein incorporated in their entireties by reference.